Frontiers in Immunology (Aug 2022)
Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome
- Grace H. Attrill,
- Grace H. Attrill,
- Grace H. Attrill,
- Hansol Lee,
- Hansol Lee,
- Hansol Lee,
- Annie T. Tasker,
- Annie T. Tasker,
- Annie T. Tasker,
- Nurudeen A. Adegoke,
- Nurudeen A. Adegoke,
- Nurudeen A. Adegoke,
- Angela L. Ferguson,
- Angela L. Ferguson,
- Angela L. Ferguson,
- Ines Pires da Silva,
- Ines Pires da Silva,
- Ines Pires da Silva,
- Ines Pires da Silva,
- Robyn P. M. Saw,
- Robyn P. M. Saw,
- Robyn P. M. Saw,
- Robyn P. M. Saw,
- John F. Thompson,
- John F. Thompson,
- John F. Thompson,
- John F. Thompson,
- Umaimainthan Palendira,
- Umaimainthan Palendira,
- Umaimainthan Palendira,
- Umaimainthan Palendira,
- Georgina V. Long,
- Georgina V. Long,
- Georgina V. Long,
- Georgina V. Long,
- Georgina V. Long,
- Peter M. Ferguson,
- Peter M. Ferguson,
- Peter M. Ferguson,
- Peter M. Ferguson,
- Richard A. Scolyer,
- Richard A. Scolyer,
- Richard A. Scolyer,
- Richard A. Scolyer,
- Richard A. Scolyer,
- James S. Wilmott,
- James S. Wilmott,
- James S. Wilmott
Affiliations
- Grace H. Attrill
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Grace H. Attrill
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Grace H. Attrill
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Hansol Lee
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Hansol Lee
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Hansol Lee
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Annie T. Tasker
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Annie T. Tasker
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Annie T. Tasker
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Nurudeen A. Adegoke
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Nurudeen A. Adegoke
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Nurudeen A. Adegoke
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Angela L. Ferguson
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Angela L. Ferguson
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Angela L. Ferguson
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
- Ines Pires da Silva
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Ines Pires da Silva
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Ines Pires da Silva
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Ines Pires da Silva
- Westmead and Blacktown Hospitals, Sydney, NSW, Australia
- Robyn P. M. Saw
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Robyn P. M. Saw
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Robyn P. M. Saw
- Royal Prince Alfred Hospital, Sydney, NSW, Australia
- Robyn P. M. Saw
- Mater Hospital, North Sydney, NSW, Australia
- John F. Thompson
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- John F. Thompson
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- John F. Thompson
- Royal Prince Alfred Hospital, Sydney, NSW, Australia
- John F. Thompson
- Mater Hospital, North Sydney, NSW, Australia
- Umaimainthan Palendira
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Umaimainthan Palendira
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Umaimainthan Palendira
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Umaimainthan Palendira
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
- Georgina V. Long
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Georgina V. Long
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Georgina V. Long
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Georgina V. Long
- Mater Hospital, North Sydney, NSW, Australia
- Georgina V. Long
- Royal North Shore Hospital, St Leonards, NSW, Australia
- Peter M. Ferguson
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Peter M. Ferguson
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Peter M. Ferguson
- Royal Prince Alfred Hospital, Sydney, NSW, Australia
- Peter M. Ferguson
- NSW Health Pathology, Sydney, NSW, Australia
- Richard A. Scolyer
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Richard A. Scolyer
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Richard A. Scolyer
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Richard A. Scolyer
- Royal Prince Alfred Hospital, Sydney, NSW, Australia
- Richard A. Scolyer
- NSW Health Pathology, Sydney, NSW, Australia
- James S. Wilmott
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- James S. Wilmott
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- James S. Wilmott
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- DOI
- https://doi.org/10.3389/fimmu.2022.979993
- Journal volume & issue
-
Vol. 13
Abstract
While the tumor immune microenvironment (TIME) of metastatic melanoma has been well characterized, the primary melanoma TIME is comparatively poorly understood. Additionally, although the association of tumor-infiltrating lymphocytes with primary melanoma patient outcome has been known for decades, it is not considered in the current AJCC melanoma staging system. Detailed immune phenotyping of advanced melanoma has revealed multiple immune biomarkers, including the presence of CD8+ T-cells, for predicting response to immunotherapies. However, in primary melanomas, immune biomarkers are lacking and CD8+ T-cells have yet to be extensively characterized. As recent studies combining immune features and clinicopathologic characteristics have created more accurate predictive models, this study sought to characterize the TIME of primary melanomas and identify predictors of patient outcome. We first phenotyped CD8+ T cells in fresh stage II primary melanomas using flow cytometry (n = 6), identifying a CD39+ tumor-resident CD8+ T-cell subset enriched for PD-1 expression. We then performed Opal multiplex immunohistochemistry and quantitative pathology-based immune profiling of CD8+ T-cell subsets, along with B cells, NK cells, Langerhans cells and Class I MHC expression in stage II primary melanoma specimens from patients with long-term follow-up (n = 66), comparing patients based on their recurrence status at 5 years after primary diagnosis. A CD39+CD103+PD-1- CD8+ T-cell population (P2) comprised a significantly higher proportion of intratumoral and stromal CD8+ T-cells in patients with recurrence-free survival (RFS) ≥5 years vs those with RFS <5 years (p = 0.013). Similarly, intratumoral B cells (p = 0.044) and a significantly higher B cell density at the tumor/stromal interface were associated with RFS. Both P2 and B cells localized in significantly closer proximity to melanoma cells in patients who remained recurrence-free (P2 p = 0.0139, B cell p = 0.0049). Our results highlight how characterizing the TIME in primary melanomas may provide new insights into how the complex interplay of the immune system and tumor can modify the disease outcomes. Furthermore, in the context of current clinical trials of adjuvant anti-PD-1 therapies in high-risk stage II primary melanoma, assessment of B cells and P2 could identify patients at risk of recurrence and aid in long-term treatment decisions at the point of primary melanoma diagnosis.
Keywords
